Research into the acute treatment of central nervous system (CNS) injury has become a national priority, and recent progress has been remarkable. Unfortunately this progress has not carried over to the less acute sequelae of CNS injury, which often include serious cognitive and motor disability. Of all diseases affecting the CNS, stroke is both the most prevalent and the primary cause of serious disability among adults. Treatment for the long-term effects of stroke lags behind treatment for the acute illness and typically focuses on developing compensatory neural circuits rather than on reinstatement of pre-existing pathways. This proposal addresses physiological remediation, in which behavior is restored by direct remodeling, aimed at reinstatement of original neural circuits. The proposal specifically focuses on methods for remediation of hand motor skill after ischemic stroke. Our approach is based on principles of functional remediation that involves restoration of function through remodeling of pre-existing motor networks. Convergent neural inputs are the functional basis of overlapping, distributed neural circuits, in which even simple behaviors are the product of a highly integrated process. Within this framework, therapeutic interventions can involve the manipulation of the intensity and diversity of interactions among elements of particular motor circuits. Motor behaviors differ in the degree to which they integrate convergent neural inputs from sensory, motor and limbic sources, and thus have different therapeutic potential for stroke patients. In this proposal we use a motor imitation therapy based on the physiology of the mirror system. The behavioral tasks studied here are skilled hand movements, which are used in the context of hand motor imitation. These tasks differ in the degree to which they harness neural circuit activity corresponding to the potential sources of sensory, motor, and associational information. All have established potential in hand motor remediation. Motor imitation consists of mental practice using external proprioceptive and visual sensory inputs and can be applied with hand motor tasks. Neural remodeling has a large potential impact after stroke. We investigate the neural remodeling that occurs with specialized late remediation-based intervention. We propose that supervised practice and specialized training with manual skill through the involvement of the motor observation-imitation system (mirror neuron system), used in a program of graded incremental complexity, will lead to notable neural circuit changes that favor recovery of impaired limbs (dominant and non-dominant). We also postulate that these neural circuit changes will be accompanied by therapeutic long-term benefits. Although we assess therapeutic benefit with primary outcome measures that reflect hand motor skill, we make extensive use of neural network modeling procedures to characterize the physiological aspects of this remediative process. [unreadable] [unreadable] [unreadable] [unreadable] [unreadable]